Project Abstract/Summary The overall goal of this research is to understand the pathophysiology of tau protein in the human central nervous system (CNS). Specifically, I will test the hypothesis that tau protein kinetics are altered in tauopathies such as Alzheimer?s disease (AD). Tau aggregation in the brain and alterations in cerebrospinal fluid (CSF) tau are hallmarks of AD and other tauopathies such as Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Previous studies suggest that CSF tau continuously increases with age and cognitive decline, and CSF total tau, CSF phosphorylated tau, and CSF amyloid beta (Ab) are currently used as AD biomarkers. However, recent study indicates that this is not linear, and CSF tau decreases after symptom onset. Therefore, it is critical to understand and evaluate tau metabolism more comprehensively in order to use it as a true biomarker that would precisely predict age of onset and progress of the disease. Currently the mechanism of CSF tau alterations, especially in humans, remains unclear. Is the increased CSF tau due to increased tau production or decreased clearance? Does pathological condition such as increasing Ab burden alter tau kinetics? To measure the tau kinetics in the human central nervous system (CNS), I developed stable isotope labeling kinetics (SILK) method for tau. In Aim 1, 30 AD patients, 40 cognitively normal age-matched participants, 30 younger controls, and up to 35 non-AD tauopathies including PSP, CBD, and MAPT mutation families will be analyzed with the tau SILK methods to test the hypothesis that tau kinetics are altered in tauopathies. In Aim 2, I will use in vitro tau SILK method in neuronal cell cultures including induced pluripotent stem cell (iPSCs)-derived neurons to test the hypothesis that tau production is increased in AD, with increasing amyloid. This proposal will help design future clinical studies and ultimately develop novel therapeutic strategies targeting tau. Successful funding of this mentored career development award will afford me an extraordinary opportunity to advance my training in clinical outcome research, leadership, and iPSC technologies. This training will equip me with the unique tools and skill sets required to excel as an independent translational scientific investigator.